Cell-based immunotherapy of prion diseases by adoptive transfer of antigen-loaded dendritic cells or antigen-primed CD4+ T lymphocytes

Abstract

Prion diseases are neurodegenerative conditions caused by the transconformation of a normal host glycoprotein, the cellular prion protein (PrPc) into a neurotoxic, self-aggregating conformer (PrPSc). TSEs are ineluctably fatal and no treatment is yet available. In principle, prion diseases could be attacked from different angles including: blocking conversion of PrPc into PrPSc, accelerating the clearance of amyloid deposits in peripheral tissues and brain, stopping prion progression in secondary lymphoid organs, reducing brain inflammation and promoting neuronal healing. There are many indications that adaptive and innate immunity might mediate those effects but so far, the achievements of immunointervention have not matched all expectations. Difficulties arise from the impossibility to diagnose TSE before substantial brain damage, poor accessibility of the CNS to immunological agents, deep immune tolerance to self-PrP, and short term effects of many immune interventions contrasting with the slow progression of TSEs. Here, we discuss two approaches, inspired from cancer immunotherapy, which might overcome some of those obstacles. One is vaccination with antigen-pulsed or antigen-transduced dendritic cells to bypass self-tolerance. The other one is the adoptive transfer of PrP-sensitized CD4+ T cells which can promote humoral, cell-mediated or regulatory responses, coordinate adaptive and innate immunity and have long lasting effects.

Acknowledgements

We thank Pauline Gourdain, Saci Iken and Martine Rosset for their inputs into the studies referred in this “Perspective.” The studies were funded by European Union Project No. FOOD-CT-2006-023144, by Groupement d’Intérêt Scientifique “Maladies à Prions,” and by INSERM and Université Pierre et Marie Curie Paris 6. V.B. was supported by a post-doctoral fellowship from INSERM.